Synthesis of 3-(4-bromophenyl)-1-morpholino-2-phenylalkan-3-ol hydrochlorides

Article abstract of DOI:10.1134/S1070428008080095

Reactions of 1-(4-bromophenyl)-3-morpholino-2-phenylpropan-1-one with various Grignard compounds in diethyl ether gave a broad series of tertiary amino alcohols, 3-(4-bromophenyl)-1-morpholino-2-phenylalkan-3-ol hydrochlorides, that can be regarded as Trihexyphenidyl analogs.

Full text of DOI:10.1134/S1070428008080095

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2008, Vol. 44, No. 8, pp. 1161–1163. © Pleiades Publishing, Ltd., 2008.
Original Russian Text © A.U. Isakhanyan, G.A. Gevorgyan, G.A. Panosyan, 2008, published in Zhurnal Organicheskoi Khimii, 2008, Vol. 44, No. 8,
pp. 1175–1177.
Synthesis of 3-(4-Bromophenyl)-1-morpholino-
2-phenylalkan-3-ol Hydrochlorides
A. U. Isakhanyana, G. A. Gevorgyana, and G. A. Panosyanb
a Mndzhoyan Institute of Fine Organic Chemistry, National Academy of Sciences of Armenia,
pr. Azatutyan 26, Erevan, 375014 Armenia
e-mail: gyulgev@gmail.com.
b Molecular Structure Research Center, National Academy of Sciences of Armenia, Erevan, Armenia
Received July 28, 2007
Abstract—Reactions of 1-(4-bromophenyl)-3-morpholino-2-phenylpropan-1-one with various Grignard com-
pounds in diethyl ether gave a broad series of tertiary amino alcohols, 3-(4-bromophenyl)-1-morpholino-2-
phenylalkan-3-ol hydrochlorides, that can be regarded as Trihexyphenidyl analogs.
DOI: 10.1134/S1070428008080095
In continuation of our studies on the synthesis of
amino ketones and the corresponding tertiary amino
alcohols [1–4] we have prepared a series of new
3-(4-bromophenyl)-1-morpholino-2-phenylalkan-3-ol
hydrochlorides and examined their antiphlogistic and
cholinolytic action. As starting compound we used
1-(4-bromophenyl)-3-morpholino-2-phenylpropan-1-
one (II) which was synthesized by the Mannich reac-
tion of 1-(4-bromophenyl)-2-phenylethanone (I) with
paraformaldehyde and morpholine in ethanol or di-
oxane. Ketone II reacted with Grignard compounds
in anhydrous diethyl ether to produce 3-(4-bromo-
phenyl)-1-morpholino-2-phenylalkan-3-ols IIIa–IIIk
which were isolated as thick oily substances and con-
verted into the corresponding hydrochlorides IVa–IVk
(Scheme 1).
The structure of hydrochlorides IVa–IVk was con-
firmed by the 1H NMR and IR spectra. The IR spectra
of initial compounds I and II contained carbonyl ab-
sorption band ν(C=O) at 1680 cm–1, whereas amino
alcohols IVa–IVk showed no absorption assignable
to carbonyl groups, but absorption bands at 3400–
3270 cm–1 were present in their IR spectra due to
stretching vibrations of the hydroxy group.
Scheme 1.
O
O
O
CH2O, HN
Br
Br
N
O
I
II
HO
R
HO
R
RMgHlg
HCl
· HCl
Br
N
Br
N
O
O
IIIa–IIIk
IVa–IVk
R = Me (a), Et (b), Pr (c), i-Pr (d), Bu (e), i-Bu (f), iso-C5H11 (g), C6H13 (h), C7H15 (i), Ph (j), cyclo-C6H11 (k).
1161

ISAKHANYAN et al.
1162
The results of biological testing of the newly syn-
7.2 Hz); 1.97 m (2H, CH2CH3); 2.63 m (1H) and 2.92–
thesized compounds will be reported elsewhere.
EXPERIMENTAL
3.22 m (3H) (NCH2); 3.41 m (1H) and 3.69 m (1H,
NCH2); 3.78–4.08 m (5H, OCH2, CH); 5.20 br (1H,
OH); 6.86–7.00 m (4H) and 7.11–7.28 m (5H) (Harom);
11.91 br (1H, HCl). Found, %: C 57.18; H 6.10;
Cl 8.03; N 3.16. C21H26 BrNO2·HCl. Calculated, %:
C 57.20; H 6.12; Cl 8.05; N 3.17.
The IR spectra were recorded on a UR-20 spec-
trometer from samples dispersed in mineral oil. The
1H NMR spectra were measured from solutions in
DMSO-d6 on a Varian Mercury-300 instrument using
tetramethylsilane as internal reference. The purity of
the products was checked by TLC on Silufol UV-254
plates (butan-1-ol–ethanol–acetic acid–water, 8:2:1:3;
development with iodine vapor.
3-(4-Bromophenyl)-1-morpholino-2-phenyl-
hexan-3-ol hydrochloride (IVc). Yield 60%, mp 218–
220°C, Rf 0.63. IR spectrum: ν 3270 cm–1 (OH).
1H NMR spectrum, δ, ppm: 0.84 m (3H, CH3); 0.79–
1.40 m (2H, CH2); 1.79–1.95 m (2H, CH2); 2.62 br
(1H) and 2.83–3.17 m (3H) (NCH2); 3.40 br (1H) and
3.60–4.10 br (6H, OCH2, CH); 5.25 br (1H, OH);
6.92 d (2H, C6H4, J = 8.7 Hz); 6.93 br (2H) and 7.14–
7.18 m (3H) (C6H5); 7.26 d (2H, C6H4, J = 8.7 Hz);
11.91 br (1H, HCl). Found, %: C 58.10; H 6.41;
Cl 7.75; N 3.11. C22H28BrNO2·HCl. Calculated, %:
C 58.08; H 6.38; Cl 7.81; N 3.08.
1-(4-Bromophenyl)-2-phenylethanone (I) [2] and
1-(4-bromophenyl)-3-morpholino-2-phenylpropan-1-
one (II) [3] were synthesized according to the proce-
dures described previously.
3-(4-Bromophenyl)-1-morpholino-2-phenylal-
kan-3-ol hydrochlorides IVa–IVk (general proce-
dure). A solution of 0.01 mol of 1-(4-bromophenyl)-3-
morpholino-2-phenylpropan-1-one (II) in 30 ml of
anhydrous diethyl ether was added dropwise to the
Grignard compound prepared from 2.4 g (0.1 mol) of
magnesium and 0.11 mol of the corresponding alkyl or
aryl halide in 50 ml of anhydrous diethyl ether. The
mixture was heated to 40–50°C and cooled to –5°C,
and 10 ml of water was slowly added in a dropwise
mode. The organic layer was separated, and the aque-
ous layer was extracted with diethyl ether (2×20 ml).
The extracts were combined with the organic phase
and dried over sodium carbonate, the drying agent was
filtered off, and 10 ml of a saturated solution of HCl in
diethyl ether was added dropwise until pH 1 (universal
indicator paper). The precipitate was filtered off and
recrystallized from anhydrous acetone.
3-(4-Bromophenyl)-4-methyl-1-morpholino-2-
phenylpentan-3-ol hydrochloride (IVd). Yield 49%,
mp 215–217°C, Rf 0.61. IR spectrum: ν 3400 cm–1
(OH). 1H NMR spectrum, δ, ppm: 0.58 d (3H, CH3, J =
6.6 Hz); 1.26 d (3H, CH3, J = 6.6 Hz); 2.01 sept (1H,
CH, J = 6.6 Hz); 2.49 m (1H) and 2.91–3.10 m (3H)
(NCH2); 3.42 m (1H), 3.46 (1H), and 3.77–4.03 m
(2H) (OCH2); 3.67 d (1H, J = 12.5 Hz) and 3.99 m
(1H) (NCH2); 4.20 d.d (1H, CH, J = 7.4, 1.8 Hz);
4.87 br (1H, OH); 6.85–7.32 m (9H, Harom); 12.00 br
(1H, HCl). Found, %: C 58.11; H 6.40; Cl 7.78; N 3.10.
C22H28 BrNO2·HCl. Calculated, %: C 58.08; H 6.38;
Cl 7.81; N 3.08.
3-(4-Bromophenyl)-1-morpholino-2-phenylhep-
tan-3-ol hydrochloride (IVe). Yield 52%, mp 215–
217°C, Rf 0.64. IR spectrum: ν 3380 cm–1 (OH).
1H NMR spectrum, δ, ppm: 0.74 m (1H) and 1.24 m
(1H, CH2); 0.82 t (3H, CH3, J = 7.2 Hz); 1.32 m (2H,
CH2); 1.90 m (2H, CH2); 2.63 m (1H) and 2.99–3.17 m
(3H) (NCH2); 3.41 m (1H) and 3.69 m (1H) (NCH2);
3.74–4.07 m (5H, OCH2, CH); 5.27 br (1H, OH);
6.91 m (2H) and 7.26 m (2H) (C6H4); 6.91 m (2H) and
7.16 m (3H) (C6H5), 11.95 br (1H, HCl). Found, %:
C 58.92; H 6.62; Cl 7.55; N 2.99. C23H30BrNO2·HCl.
Calculated, %: C 58.91; H 6.61; Cl 7.57; N 2.98.
3-(4-Bromophenyl)-1-morpholino-2-phenylbu-
tan-3-ol hydrochloride (IVa). Yield 77%, mp 238–
240°C, Rf 0.63. IR spectrum: ν 3310 cm–1 (OH).
1H NMR spectrum, δ, ppm: 1.64 s (3H, CH3); 2.70 br
(1H), 2.92 br (1H), and 3.06 br (2H) (NCH2); 3.38 br
(1H) and 3.65–4.00 m (6H) (OCH2, CHCH2); 5.50 br
(1H, OH); 6.98 m (2H) and 7.10–7.14 m (3H) (C6H5);
7.00–7.24 d (4H, C6H4, J = 8.7 Hz); 11.67 br (1H,
HCl). Found, %: C 56.13; H 5.70; Cl 8.24; N 3.19.
C20H24 BrNO2·HCl. Calculated, %: C 56.27; H 5.86;
Cl 8.32; N 3.28.
3-(4-Bromophenyl)-5-methyl-1-morpholino-2-
phenylhexan-3-ol hydrochloride (IVf). Yield 41%,
mp 214–216°C, Rf 0.63. IR spectrum: ν 3290 cm–1
(OH). Found, %: C 58.90; H 6.60; Cl 7.56; N 2.97.
C23H30BrNO2·HCl. Calculated, %: C 58.91; H 6.61;
Cl 7.57; N 2.98.
3-(4-Bromophenyl)-1-morpholino-2-phenylpen-
tan-3-ol hydrochloride (IVb). Yield 66%, mp 210–
212°C, Rf 0.62. IR spectrum: ν 3290 cm–1 (OH).
1H NMR spectrum, δ, ppm: 0.68 t (3H, CH3, J =
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 44 No. 8 2008

SYNTHESIS OF 3-(4-BROMOPHENYL)-1-MORPHOLINO-2-PHENYLALKAN-3-OL
1163
(C6H4); 6.91 m (2H) and 7.16 m (3H) (C6H5); 11.95 br
(1H, HCl). Found, %: C 61.13; H 7.32; Cl 6.70;
N 2.75. C26H36BrNO2·HCl. Calculated, %: C 61.12;
H 7.30; Cl 6.98; N 2.74.
3-(4-Bromophenyl)-6-methyl-1-morpholino-2-
phenylheptan-3-ol hydrochloride (IVg). Yield 70%,
mp 202–204°C, Rf 0.63. IR spectrum: ν 3280 cm–1
1
(OH). H NMR spectrum, δ, ppm: 0.64 m (1H) and
1.29 m (1H) (CH2); 0.78 d (3H, CH3, J = 6.6 Hz);
0.85 d (3H, CH3, J = 6.6 Hz ); 1.45 m (1H, CH, J =
6.6 Hz); 1.91 m (2H, CH2); 2.63 m (1H) and 2.97–
3.16 m (3H) (NCH2); 3.41 m (1H) and 3.70 m (1H)
(NCH2); 3.74–4.07 m (5H, OCH2, CH); 5.25 br (1H,
OH); 6.89 m (2H) and 7.26 m (2H) (C6H4); 6.90 m
(2H) and 7.16 m (3H) (C6H5); 11.90 br (1H, HCl).
Found, %: C 59.67; H 6.82; Cl 7.36; N 2.91.
C24H32BrNO2·HCl. Calculated, %: C 59.68; H 6.83;
Cl 7.35; N 2.90.
3-(4-Bromophenyl)-1-morpholino-2,3-diphenyl-
propan-3-ol hydrochloride (IVj). Yield 73%,
mp 220–222°C, Rf 0.60. IR spectrum: ν 3330 cm–1
(COH). 1H NMR spectrum, δ, ppm: 2.55 br (1H) and
2.96 br (3H) (NCH2); 3.32 br.d (1H, J = 13.5 Hz) and
4.08 br (1H) (NCH2); 3.51–3.96 br.m (4H, OCH2);
4.92 br (1H, CH); 5.95 br (1H, OH); 7.01–7.15 m
(7H), 7.24–7.3 t (1H), 7.33 m (2H), 7.40 t (2H, J =
7.7 Hz), and 7.97 br.d (2H, J = 7.8 Hz) (Harom); 2.90 br
(1H, HCl). Found, %: C 61.40; H 5.51; Cl 7.27;
N 2.85. C25H26BrNO2·HCl. Calculated, %: C 61.41;
H 5.52; Cl 7.26; N 2.86.
3-(4-Bromophenyl)-1-morpholino-2-phenylnon-
an-3-ol hydrochloride (IVh). Yield 69%, mp 211–
213°C, Rf 0.62. IR spectrum: ν 3390 cm–1 (OH).
1H NMR spectrum, δ, ppm: 0.75 m (1H) and 1.37 m
(1H) (CH2); 0.84 t (3H, CH3, J = 6.9 Hz); 1.13–1.28 m
(6H, CH2); 1.80–1.97 m (2H, CH2); 2.63 m (1H),
3.00 m (2H), and 3.41 m (1H, NCH2); 3.11 d.d (1H,
J = 3.7, 8.0 Hz) and 3.80 d.d (1H, J = 13.7, 2.9 Hz)
(NCH2); 3.64–4.08 m (5H, OCH2, CH); 5.25 br (1H,
OH); 6.90 m (2H) and 7.26 m (2H) (C6H4); 6.91 m
(2H) and 7.17 m (3H) (C6H5); 11.94 br (1H, HCl).
Found, %: C 60.41; H 7.03; Cl 7.16; N 2.80.
C25H34 BrNO2·HCl. Calculated, %: C 60.42; H 7.04;
Cl 7.15; N 2.81.
3-(4-Bromophenyl)-3-cyclohexyl-1-morpholino-
2-phenylpropan-3-ol hydrochloride (IVk). Yield
59%, mp 198–200°C, Rf 0.62. IR spectrum:
1
ν 3380 cm–1 (OH). H NMR spectrum, δ, ppm: 0.91–
1.64 m (10H) and 1.92 m (1H) (C6H11); 2.36 m (1H)
and 2.79–3.09 m (3H) (NCH2); 3.40 br (2H, NCH2);
3.80 m (4H, OCH2); 4.09 m (1H, CH); 5.01 br (1H,
OH); 6.91 m (4H), 7.20 m (3H), and 7.27 m (2H)
(Harom); 11.86 br (1H, HCl). Found, %: C 60.66;
H 6.65; Cl 7.22; N 2.81. C25H32 BrNO2·HCl. Calculat-
ed, %: C 60.67; H 6.67; Cl 7.18; N 2.83.
REFERENCES
3-(4-Bromophenyl)-1-morpholino-2-phenyldec-
an-3-ol hydrochloride (IVi). Yield 72%, mp 205–
207°C, Rf 0.63. IR spectrum: ν 3380–3250 cm–1 (OH).
1H NMR spectrum, δ, ppm: 0.75 m (1H) and 1.37 m
(1H) (CH2); 0.85 t (3H, CH3, J = 6.9 Hz); 1.13–1.29 m
(8H, CH2); 1.79–1.96 m (2H, CH2); 2.62 m (1H),
2.99 m (2H), and 3.39 m (1H) (NCH2); 3.10 m (1H)
and 3.68 m (1H) (NCH2); 3.62–4.07 m (5H, CH2, CH);
5.25 br (1H, OH); 6.90 m (2H) and 7.26 m (2H)
1. Gevorgyan, G.A., Isakhanyan, A.U., Panosyan, G.A., and
Tumadzhyan, A.E., Khim.-Farm. Zh., 2003, vol. 37,
p. 45.
2. Gasparyan, N.K., Gevorgyan, G.A., Isakhanyan, A.U.,
and Tumadzhyan, A.E., Khim. Zh. Arm., 2003, vol. 56,
p. 58.
3. Isakhanyan, A.U., Khim. Zh. Arm., 2005, vol. 58, p. 94.
4. Gevorgyan, G.A. Khim. Zh. Arm., 2006, vol. 59, p. 137.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 44 No. 8 2008